title: JNK and macroautophagy activation by bortezomib has a pro-survival effect in primary effusion lymphoma cells.
abstract: Understanding the mechanisms of autophagy induction and its role during chemotherapeutic treatments is of fundamental importance in order to manipulate it to improve the outcome of chemotherapy. In particular whether the bortezomib-induced autophagy plays a pro-survival or pro-death role is still controversial. In this study we investigated if bortezomib induced endoplasmic reticulum (ER) stress and activated autophagy in Primary Effusion Lymphoma (PEL) cells and how they influenced cell survival. We found that bortezomib induced up-regulation of the pro-survival and pro-death ER stress molecules BIP and CHOP and activated c-Jun NH2-terminal kinase (JNK), resulting in Bcl-2 phosphorylation and induction of autophagy. JNK and autophagy activation played a pro-survival role in this setting, thus their inhibition increased the bortezomib cytotoxic effect and PARP cleavage in PEL cells. Based on our results we suggest that the combination of bortezomib with JNK or autophagy inhibitors could be exploited to improve the outcome of therapy of this aggressive B cell lymphoma.
authors.affiliation: Department of Experimental Medicine, Istituto Pasteur Fondazione Cenci Bolognetti, La Sapienza University, Rome, Italy.
authors.forename: Marisa
authors.initials: M
authors.lastname: Granato
authors.forename: Roberta
authors.initials: R
authors.lastname: Santarelli
authors.forename: Lavinia V
authors.initials: LV
authors.lastname: Lotti
authors.forename: Livia
authors.initials: L
authors.lastname: Di Renzo
authors.forename: Roberta
authors.initials: R
authors.lastname: Gonnella
authors.forename: Alessia
authors.initials: A
authors.lastname: Garufi
authors.forename: Pankaj
authors.initials: P
authors.lastname: Trivedi
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.forename: Gabriella
authors.initials: G
authors.lastname: D'Orazi
authors.forename: Alberto
authors.initials: A
authors.lastname: Faggioni
authors.forename: Mara
authors.initials: M
authors.lastname: Cirone
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D054685:Lymphoma, Primary Effusion / Q000201:enzymology / Q000276:immunology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008854:Microscopy, Electron; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C481505:BCL2L15 protein, human; D001897:Boronic Acids; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D000069286:Bortezomib; D048670:MAP Kinase Kinase 4